Several patents have disclosed various methods of producing 2β-substituted methyl-2α-methyl penicillin derivatives of the formula (II), but none of the patents disclosed the process using the intermediate of formula (I).
Tanaka et. al (Bull. Chem. Soc. Japan 62, 3046-3048 (1989)) describes a facile halogenative cyclization of 4-(2-benzothiazolyldithio)azetidinones and the susceptibility of 2-bromomethyl penams to isomerization to produce 3-bromocephams. The process reported that nitrosyl halide, generated from sodium nitrite and hydrogen halide in a biphasic water-dichloromethane medium, is shown to nitrosate the benzothiazolyl-nitrogen of the azetidinone derivative, thereby effecting the leaving of benzothiazolylthio group and forming the 2β-halomethylpenam.
The present invention is based on the mechanism that the protic acid itself directly reacts with the 4-(benzothiazolyldithio)azetidinone in a solvent to produce the cepham derivative, along with the by-product, 2-mercaptobenzothiazole. The 2-mercaptobenzothiazole was oxidized, by the addition of sodium nitrite, into 2,2′-dithiobis(benzothiazole), which is easier to remove from the reaction mixture owing to its less soluble nature and enable isolation of the cephem derivative.